Despite decades of intensive scientific and clinical research, cancer remains a challenging disease to both the patient and the healthcare provider. In the U.S. alone, it is estimated that there are over 1.5 million new cases of cancer and more than half million of cancer-related deaths in 2011. Worldwide, cancer is the third leading cause of death.
Cancer is characterized by rapidly-proliferating cell growth in the body. Cancer is often able to invade other tissues from its original location and, in a process called metastasis, spread to other parts of the body through blood and lymphatics. There are many types of cancer, which may be classified in pathology and clinical diagnosis into carcinoma, sarcoma, leukemia, lymphoma and myeloma, and malignant tumors of the central nervous system.
At the present time, the leading therapies for cancer include surgery, radiation, and chemotherapy. Surgery and radiotherapy are quite successful in treating primary tumors. However, once a cancer has disseminated to distant sites, chemotherapy is often required to treat the disease. Cytotoxic agents have played a critical role in modern cancer therapy. However, they usually induce substantial toxicity in normal tissues. Targeted therapies that more specifically target cancer cells are more desirable. A relatively new class of agents with selectivity for targets implicated in tumor growth have started to emerge recently, demonstrating impressive efficacy with much less toxicity than cytotoxic agents.
Protein kinases represent potential targets for therapeutic inhibition. (Pyle, et al., 2006 Nat Biotechnol. 24(3): p. 344-50.) Protein kinases are a family of enzymes that regulate a wide variety of cellular processes, including cell growth, cell proliferation, cell differentiation and metabolism. A kinase enzyme that modifies other proteins by chemically adding phosphate groups to them in a phosphorylation process. Protein kinases communicate cell growth signals through sequential chemical modification of pathway partners. Therefore, pharmacologic inhibition of any kinase on a given signal transduction cascade would theoretically block communication along the entire pathway. In addition, it is known that protein kinases play a role in disease states and disorders, for example, kinase mutation and/or overexpression are frequently characterized in cancers, resulting in hyperactivated activity that often correlates with uncontrolled cell growth.
Cancer Stem Cells (CSC) is a subpopulation of cells within a variety of tumor types with a tumorigenic potential that is lacking in the rest of the cells within these tumors. CSC can generate tumors through the stem cell processes of self-renewal and differentiation into multiple cell types. There is mounting evidence that such cells exist in almost all tumor types. CSC give rise to the differentiated cells that form the bulk of the tumor mass and phenotypically characterize the disease. Cancer stem cells have been demonstrated to be fundamentally responsible for carcinogenesis, cancer metastasis, and cancer reoccurrence. In many tumors, CSC and their differentiated progeny appear to have markedly different biologic characteristics.
Therapies specifically targeted at CSCs, therefore, hold unique potential for improvement of survival and quality of life of cancer patients, especially for sufferers of metastatic disease. (PCTUS2008075418, WO 2009033033) Conventional therapies that target mature tumor cells may lead to clinical improvement, but are unlikely to be curative unless CSCs are also targeted. Relevant targets unique to the rare cancer stem cells may be missed if clinical activity is judged solely by criteria that reflect the effects of treatment on the bulk of the cancer.
Recent studies have shown that certain compounds inhibit kinases and kill cancer stem cells, demonstrating that kinases are important targets for killing or inhibiting cancer stem cells. These kinases important for CSCs are collectively referred to cancer stem cell pathway kinase (CSCPK) hereinafter. Our results provide a method of targeting cancer stem cells with CSCPK inhibitors.
PDGFRα is a receptor tyrosine kinase (RTK) that is activated after binding to its ligand, PDGF, which contributes to cell proliferation, angiogenesis, and apoptosis. It belongs to class III receptor tyrosine kinase family and are related to the CFS-1 receptor/c-fms and the stem cell growth factor/c-kit proto-oncogene family. PDGFRα pathway is active in early fetal development and reactivated in many cancers, such as hepatocellular cancer (HCC), head and neck cancer, brain tumors, gastrointestinal tumors, skin cancer, prostate cancer, ovarian cancer, breast cancer, sarcoma, and leukemia. (Betsholtz 1995 Int J Dev Biol 39(5): p. 817-25; Chott, et al. 1999 Am J Pathol 155(4): p. 1271-9; Dabrow, et al., 1998 Gynecol Oncol 71(1): p. 29-37; Cools, et al. 2003 N Engl J Med 348(13): p. 1201-14; Heinrich, et al., 2003 Science 299(5607): p. 708-10; Holtkamp, et al. 2006 Carcinogenesis 27(3): p. 664-71; Jackson, et al. 2006 Neuron 51(2): p. 187-99; Jechlinger, et al. 2006 J Clin Invest 116(6): p. 1561-70; Ongkeko, et al. 2005 Am J Clin Pathol 124(1): p. 71-6; Stock, et al. 2007 Mol Cancer Ther 6(7): p. 1932-41; Sulzbacher, et al. 2003 Mod Pathol 16(1): p. 66-71; Wilczynski, et al. 2005 Hum Pathol 36(3): p. 242-9; Zhang, et al. 2005 Clin Cancer Res 11(24 Pt 1): p. 8557-63; Westermark, et al. 1993 Acta Oncol 32(2): p. 101-5.)
In addition, PDGFRα activation has recently been shown to play a key role in bone metastasis of prostate cancer. (Dolloff, et al. 2005 Oncogene 24(45): p. 6848-54; Dolloff, et al. 2007 Cancer Res 67(2): p. 555-62.) Furthermore, PDGFRα-p70S6K pathway has been shown to be essential for angiogenesis in vivo. (Tsutsumi, et al. 2004 Circ Res 94(9): p. 1186-94.) Specifically targeting PDGFRα using monoclonal antibody has been shown to lead to significant reduction in tumor cell proliferation and survival while being a relatively non-toxic treatment. (Stock, et al. 2007 Mol Cancer Ther 6(7): p. 1932-41.) Therefore, PDGFRα represents a target for developing targeted chemotherapy against broad spectrum of cancers with less toxicity.
Other than cancer, it has been well demonstrated that chromosomal rearrangements activate PDGFRα by fusion to FIP1L1, causing idiopathic hypereosinophilic syndrome. (Cools, et al. 2003 N Engl J Med 348(13): p. 1201-14.) In addition, activation of PDGFRα by promoter polymorphisms has linked to neural tube defects including spina bifida, which has been verified by mouse mutant model. (Joosten, et al. 2001 Nat Genet 27(2): p. 215-7.) PDGFRα activation has also been linked with fibrosis. (Lasky, et al. 1998 Am J Respir Crit Care Med 157(5 Pt 1): p. 1652-7; Ferns, et al. 1991 Science 253(5024): p. 1129-32; Johnson, et al. 1992 J Exp Med 175(5): p. 1413-6; Raines, et al. 1989 Science 243(4889): p. 393-6.) Thus, PDGFRα is a potential target for anti-fibrotic therapy.
There are continued unmet needs for novel inhibitors of cancer stem cells as well as cancer stem cell pathway kinase and other related kinases and targets.